Andrew I. Rutherford

Biosimilars in rheumatology: out of the laboratory and into practice

In 2015, the rheumatology community saw the emergence of the first biosimilar products onto the market. Although biosimilars are not new to the medical community at large, their arrival into the field of rheumatology is new and comes with great anticipation. Infliximab (Remicade) first received a European license in August 1999. The patent on Remicade expired in February 2015. In March 2015, two infliximab biosimilars were launched in the UK simultaneously: Remsima (NAPP Pharmaceuticals) and Inflectra (Hospira). Both contain the same biological productmanufactured by Celltrion, the only difference being themarketing company. The National Health Service (NHS) list price for 100 mg vial of these compounds is £377.66 pence compared with Remicade, which is marketed at £419.62 pence [1]. Local agreements further reduced the cost, with discounts approaching 50% of the cost of the original Remicade price. In February 2016, the US Food and Drug Association (FDA) voted to approve Celltrion’s infliximab biosimilar in the US across all seven indications that Remicade holds a license for [2]. In the UK, the etanercept (Enbrel) patent expired in November 2015 and the first etanercept biosimilar was licensed in January 2016. The situation in the US is more complex. The original Enbrel patents were filed in 1995 but due to several delays were not approved until 2011. Previous legislation granted patent protection from the date of approval rather than the date of application. While this legislation has now changed, the Enbrel patents were filed under the old legislation. Roche, who own the patents, are claiming protection until 2028 but this is being contested by Novartis who have their own etanercept biosimilar currently awaiting FDA approval.

Opportunistic infections in rheumatoid arthritis patients exposed to biologic therapy: results from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis

Objectives This analysis set out to estimate the risk of opportunistic infection (OI) among patients with RA by biologic class. Methods The British Society for Rheumatology Biologics Register for Rheumatoid Arthritis is a prospective observational cohort study established to evaluate safety of biologic therapies. The population included adults commencing biologic therapy for RA. The primary outcome was any serious OI excluding tuberculosis (TB). Event rates were compared across biologic classes using Cox proportional hazards with adjustment for potential confounders identified a priori. Analysis of the incidence of TB was performed separately. Results In total, 19 282 patients with 106 347 years of follow-up were studied; 142 non-TB OI were identified at a rate of 134 cases/100 000 patient years (pyrs). The overall incidence of OI was not significantly different between the different drug classes; however, the rate of Pneumocystis infection was significantly higher with rituximab than with anti-TNF therapy (adjusted hazard ratio = 3.2, 95% CI: 1.4, 7.5). The rate of TB fell dramatically over the study period (783 cases/100 000 pyrs in 2002 to 38 cases/100 000 pyrs in 2015). The incidence of TB was significantly lower among rituximab users than anti-TNF users, with 12 cases/100 000 pyrs compared with 65 cases/100 000 pyrs. Conclusions The overall rate of OI was not significantly different between drug classes; however, a subtle difference in the pattern of OI was seen between the cohorts. Patient factors such as age, gender and comorbidity were the most important predictors of OI.

Serious infection across biologic-treated patients with rheumatoid arthritis: results from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis

Objectives To compare the incidence of serious infection (SI) across biologic drugs used to treat rheumatoid arthritis (RA) using data from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis (BSRBR-RA). Methods The BSRBR-RA is a prospective observational cohort study. This analysis included patients with RA starting a new biologic. The primary outcome was SI defined as an infectious event requiring admission to hospital, intravenous antibiotics or resulting in death. Event rates were calculated and compared across biologics using Cox proportional hazards with adjustment for potential confounders. Secondary outcomes were the rate of infection by organ class and 30-day mortality following infection. Results This analysis included 19 282 patients with 46 771 years of follow-up. The incidence of SI was 5.51 cases per 100 patient years for the entire cohort (95% CI 5.29 to 5.71). Compared with etanercept, tocilizumab had a higher risk of SI (HR 1.22, 95% CI 1.02 to 1.47) and certolizumab pegol a lower risk of SI (HR 0.75, 95% CI 0.58 to 0.97) in the fully adjusted model. The 30-day mortality following SI was 10.4% (95% CI 9.2% to 11.6%). Conclusions The rate of SI was lower with certolizumab pegol than etanercept in the primary analysis but the result was no longer significant in several sensitivity analyses performed suggesting residual confounding may account for the observed difference. From these results, it would be wrong to conclude that certolizumab pegol has a lower rate of SI than other biologics; however, the risk does not appear to be significantly higher as has previously been suggested.

Recurrent serious infections in patients with rheumatoid arthritis—results from the British Society for Rheumatology Biologics Register

Objectives To establish the rate of recurrent infection in RA patients recruited to the British Society for Rheumatology Biologics Register - Rheumatoid Arthritis. Secondary objectives were to establish whether the organ class of index infection predicted future serious infection (SI). Methods Using data from the British Society for Rheumatology Biologics Register - Rheumatoid Arthritis, a prospective observational cohort, we identified patients with at least one episode of SI. Incidence rates of SI, recurrent SI within the same organ class as the index infection and recurrent SI (of any class) were calculated. A Cox proportional hazards model was used to identify predictors of SI. Results In total, 5289 subjects with at least one SI contributing 19 431 patient-years follow-up were studied. The baseline annual rate of first SI was 4.6% (95% CI: 4.5, 4.7), increasing to 14.1% (95% CI: 13.5, 14.8) following an index infection. Respiratory infections were the most frequent (44% of all events). Recurrent infections mirrored the organ class of the index infection. Sepsis, increasing age and polypharmacy were significant predictors of infection recurrence in a fully adjusted model. The system class of index infection was associated with the risk of a recurrent event; subjects who experienced sepsis had the highest risk of subsequent SI within 12 months, 19.7% (95% CI: 15.1, 25.7). Conclusion Recurrent infections in RA are common. Understanding patterns and predictors of recurrent infection together with the differential infection risk associated with immunosuppressive agents will help personalize RA care, tailor treatment choices better and mitigate against episodes of SI.

Biologic Prescribing Decisions Following Serious Infection; Results from the British Society for Rheumatology Biologics Register – Rheumatoid Arthritis (BSRBR-RA)

Objectives To establish whether the decision to stop, continue or switch TNF inhibitor (TNFi) therapy to a biologic drug with an alternative mode of action following a serious infection (SI) impacts upon the risk of recurrent SI in patients with RA. Methods Patients recruited to the British Society for Rheumatology Biologics Register-RA with at least one episode of SI while on TNFi were included. The biologic treatment decision following SI was considered. A multivariable adjusted Cox proportional hazards model was used to identify predictors of recurrent SI and whether biologic treatment choices influenced future SI risk. Results In total, 1583 patients suffered at least one SI while on TNFi. Most patients (73%) were recorded as continuing TNFi 60 days after an index SI. The rate of recurrent SI was 25.6% per annum (95% CI: 22.5, 29.2%). The rate of recurrent SI was highest in patients who stopped their TNFi (42.6% per annum, 95% CI: 32.5, 55.7%) and lowest in those who switched biologic drug class (12.1% per annum, 95% CI: 3.9, 37.4%). Compared with patients stopping biologic therapy, patients who continued or switched drug class had significantly lower risk of recurrent SI (drug continuation hazard ratio = 0.54, 95% CI: 0.40, 0.74; drug switch hazard ratio = 0.29, 95% CI: 0.09, 0.95). Conclusions Patients who continued or switched their TNFi post-index SI had a lower risk of recurrent SI infection compared with those who stopped the drug. This may be explained by better control of disease activity with reintroduction of biologic therapy, a driving factor for SI or alternatively channelling fitter patients to restart biologic therapy.

Differentiating Disease Flare From Infection: A Common Problem in Rheumatology. Do 18F-FDG PET/CT Scans and Novel Biomarkers Hold The Answer?

Purpose of reviewFever is common within rheumatology but it is often challenging to identify its source. To do so correctly is paramount in patients with an underlying inflammatory condition receiving immunosuppressive therapy. This review article looks at the available evidence and merits of both 18F-fluoro-deoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) scans and new proposed biomarkers in determining the cause of fever within rheumatology.Recent findings18F-FDG PET/CT scans are already an established tool in the detection and diagnosis of malignancy and are emerging for use in fever of unknown origin. More recently, they have been used to identify rheumatological causes of fever such as large vessel vasculitis and adult-onset Still’s disease. Within these conditions, biomarkers such as procalcitonin and presepsin may help to differentiate endogenous from exogenous pyrogens.Summary18F-FDG PET/CT scanning shows promise in locating the source of pyrogens and may be superior to other conventional forms of imaging. As evidence and test availability increases, its use is likely to become commonplace in the diagnostic work-up of fever. Once a source is located, selected biomarkers may be used to confirm a cause.